Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a pivotal role in this physioxic environment. In normoxic conditions, HIFs are downregulated, whereas in physioxic conditions, they are upregulated. The HIF-α family comprises three members: HIF-1α, HIF-2α, and HIF-3α. Each member has a distinct function in articular cartilage. In osteoarthritis, which is primarily caused by degeneration of articular cartilage, HIF-1α is upregulated in chondrocytes and is believed to protect articular cartilage by acting anabolically on it. Conversely, in contrast to HIF-1α, HIF-2α exerts a catabolic influence on articular cartilage. It may therefore be possible to develop a new treatment for OA by controlling the expression of HIF-1α and HIF-2α with drugs or by altering the oxygen environment in the joints.

Background/Objectives: Medial open wedge high tibial osteotomy (MOWHTO) has led to favorable clinical results since the introduction of locking plates. Surgical indications, techniques, and postoperative alignment are crucial for achieving favorable clinical outcomes. This study analyzed the clinical outcomes of patients after >5 years of post-MOWHTO follow-up to identify the influential factors. Methods: Thirty-nine patients (48 knees) underwent MOWHTO for medial compartment knee osteoarthritis or -necrosis and were followed up for >5 years. The targeted postoperative % mechanical axis (%MA) was 62.5% (Fujisawa point). The Japanese Orthopaedic Association (JOA) Knee Disease Outcome Criteria score; Kellgren–Lawrence classification; hip-knee-ankle, medial proximal tibial, mechanical lateral distal femoral, and joint line convergence angles (JLCA); and %MA were evaluated preoperatively, at implant removal, and at the final follow-up. Total knee arthroplasty (TKA) was the survival endpoint. Uni- and multivariate analyses were performed to identify the factors influencing survival rates. Results: The mean JOA score improved from preoperative to implant removal and was sustained at 102 months. Four of the 48 knees required TKA, resulting in a 10-year survival rate of 82%. Body mass index, preoperative JLCA, and Δ%MA influenced the post-MOWHTO survival rate. The Δ%MA was significantly greater in the group with a %MA < 62.5% at implant removal. Conclusions: MOWHTO with a target %MA of 62.5% yielded favorable long-term outcomes. Additionally, preoperative obesity and high joint instability negatively influenced post-MOWHTO survival. Furthermore, a postoperative %MA of < 62.5% is associated with difficulty maintaining stable alignment and an increased risk of conversion to TKA.

The effects of treadmill running under hypoxic conditions on joints and muscles of collagen-induced arthritis (CIA) rats were investigated. CIA rats were divided into normoxia no-exercise, hypoxia no-exercise (Hypo-no), and hypoxia exercise (Hypo-ex) groups. Changes were examined on days 2 and 44 of hypoxia with or without treadmill exercises. In the early stage of hypoxia, the expression of hypoxia-inducible factor (HIF)-1α increased in the Hypo-no and Hypo-ex groups. The expression of the egl-9 family hypoxia-inducible factor 1 (EGLN1) and vascular endothelial growth factor (VEGF) in the Hypo-ex group also increased. Under sustained hypoxia, the Hypo-no and Hypo-ex groups did not show increased expression of HIF-1α or VEGF, but p70S6K levels were elevated. Histologically, joint destruction was alleviated in the Hypo-no group, the loss of muscle weight in slow-twitch muscles was prevented, and muscle fibrosis was suppressed. In the Hypo-ex group, the preventive effect of a reduction in the slow-twitch muscle cross-sectional area was enhanced. Thus, chronic hypoxia in an animal model of rheumatoid arthritis controlled arthritis and joint destruction and prevented slow-twitch muscle atrophy and fibrosis. The combination of hypoxia with treadmill running further enhanced the preventive effects on slow-twitch muscle atrophy.

Bone marrow stimulation is a treatment for articular cartilage injuries that promotes cartilage repair by inducing the migration and accumulation of mesenchymal stem cells (MSCs), but often results in fibrocartilage with limited durability. This study aimed to investigate the effect of hypoxic conditions on cartilage repair using a rat osteochondral defect model. Osteochondral defects (1.0 mm in diameter) were created in the femoral trochlear groove, and rats were exposed to hypoxic conditions (12% O₂) for 4 weeks postoperatively. Histological analysis was performed, and protein expression of hypoxia-inducible factor-1α (HIF-1α) and SRY-box transcription factor 9 (SOX9) in the repair tissue was evaluated after 1 week. As a result, after 1 week, protein expression of HIF-1α and SOX9 in the Hypoxia group was significantly increased compared to the Normoxia group. After 4 weeks, the Hypoxia group exhibited a hyaline cartilage-like tissue structure with a significantly lower Modified Wakitani score compared to the Normoxia group. Furthermore, after 4 weeks, the inhibition of HIF-1α suppressed cartilage repair. These findings suggest that hypoxic conditions promote SOX9 expression via HIF-1α during the early phase of MSC chondrogenic differentiation and promote the formation of hyaline cartilage-like repair tissue. In conclusion, bone marrow stimulation under hypoxic conditions may enhance the repair effect on articular cartilage injuries.

Although the moderate thermal stimulation of articular cartilage exerts chondroprotective effects, it is difficult to effectively heat deep articular cartilage with conventional methods. Photosensitizers increase the ambient temperature using near-infrared (NIR) radiation, which has high tissue permeability. We hypothesized that the intra-articular administration of photosensitizers and NIR irradiation would exert a greater heating effect on articular cartilage. We aimed to evaluate the heating effect of this method on cultured chondrocytes and rat knee cartilage. In vitro, we irradiated a photosensitizer-containing medium with NIR and measured changes in the medium temperature, cytotoxicity, and gene expression of heat shock protein (HSP) 70 and aggrecan (ACAN). In vivo, the knee joints of rats treated with photosensitizers were irradiated with NIR, and changes in intra-articular temperature and gene expression were measured, alongside histological analysis. The results showed that the medium and intra-articular temperature were raised to approximately 40 °C with no apparent disruption to articular cartilage or the immunohistochemically enhanced staining of HSP70 in chondrocytes. The gene expression of HSP70 and ACAN was increased in both cultured and articular cartilage. In summary, this method can safely heat joints and enhance cartilage metabolism by inducing HSP70 expression in articular cartilage. It presents a new hyperthermia therapy with effective cartilage protection.

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA.